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. 1992 Aug;106(4):958–965. doi: 10.1111/j.1476-5381.1992.tb14442.x

Actions and mechanisms of action of novel analogues of sotalol on guinea-pig and rabbit ventricular cells.

S P Connors 1, E W Gill 1, D A Terrar 1
PMCID: PMC1907682  PMID: 1393293

Abstract

1. The actions and mechanisms of action of novel analogues of sotalol which prolong cardiac action potentials were investigated in guinea-pig and rabbit isolated ventricular cells. 2. In guinea-pig and rabbit cells the compounds significantly prolonged action potential duration at 20% and 90% repolarization levels without affecting resting membrane potential. In guinea-pig but not rabbit cells there was an increase in action potential amplitude and in rabbit cells there was no change in the shape or position of the 'notch' in the action potential. 3. Possible mechanisms of action were studied in more detail in the case of compound II (1-(4-methanesulphonamidophenoxy)-3-(N-methyl 3,4 dichlorophenylethylamino)-2-propanol). Prolongation of action potential duration continued to occur in the presence of nisoldipine, and calcium currents recorded under voltage-clamp conditions were not reduced by compound II (1 microM). Action potential prolongation by compound II was also unaffected in the presence of 10 microM tetrodotoxin. 4. Compound II (1 microM) did not influence IK1 assessed from the current during ramp changes in membrane potential (20 mV s-1) over the range -90 to -10 mV. 5. Compound II (1 microM) blocked time-dependent delayed rectifier potassium current (IK) activated by step depolarizations and recorded as an outward tail following repolarization. When a submaximal concentration (50 nM) was applied there was no change in the apparent reversal potential of IK.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. Bennett P. B., McKinney L. C., Kass R. S., Begenisich T. Delayed rectification in the calf cardiac Purkinje fiber. Evidence for multiple state kinetics. Biophys J. 1985 Oct;48(4):553–567. doi: 10.1016/S0006-3495(85)83813-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Beuckelmann D. J., Wier W. G. Sodium-calcium exchange in guinea-pig cardiac cells: exchange current and changes in intracellular Ca2+. J Physiol. 1989 Jul;414:499–520. doi: 10.1113/jphysiol.1989.sp017700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Boyett M. R., Jewell B. R. Analysis of the effects of changes in rate and rhythm upon electrical activity in the heart. Prog Biophys Mol Biol. 1980;36(1):1–52. doi: 10.1016/0079-6107(81)90003-1. [DOI] [PubMed] [Google Scholar]
  4. Carmeliet E. Electrophysiologic and voltage clamp analysis of the effects of sotalol on isolated cardiac muscle and Purkinje fibers. J Pharmacol Exp Ther. 1985 Mar;232(3):817–825. [PubMed] [Google Scholar]
  5. Connors S. P., Dennis P. D., Gill E. W., Terrar D. A. The synthesis and potassium channel blocking activity of some (4-methanesulfonamidophenoxy)propanolamines as potential class III antiarrhythmic agents. J Med Chem. 1991 May;34(5):1570–1577. doi: 10.1021/jm00109a007. [DOI] [PubMed] [Google Scholar]
  6. Cross P. E., Arrowsmith J. E., Thomas G. N., Gwilt M., Burges R. A., Higgins A. J. Selective class III antiarrhythmic agents. 1 Bis(arylalkyl)amines. J Med Chem. 1990 Apr;33(4):1151–1155. doi: 10.1021/jm00166a011. [DOI] [PubMed] [Google Scholar]
  7. Delmar M., Glass L., Michaels D. C., Jalife J. Ionic basis and analytical solution of the wenckebach phenomenon in guinea pig ventricular myocytes. Circ Res. 1989 Sep;65(3):775–788. doi: 10.1161/01.res.65.3.775. [DOI] [PubMed] [Google Scholar]
  8. Ehara T., Noma A., Ono K. Calcium-activated non-selective cation channel in ventricular cells isolated from adult guinea-pig hearts. J Physiol. 1988 Sep;403:117–133. doi: 10.1113/jphysiol.1988.sp017242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fedida D., Shimoni Y., Giles W. R. A novel effect of norepinephrine on cardiac cells is mediated by alpha 1-adrenoceptors. Am J Physiol. 1989 May;256(5 Pt 2):H1500–H1504. doi: 10.1152/ajpheart.1989.256.5.H1500. [DOI] [PubMed] [Google Scholar]
  10. Giles W. R., Imaizumi Y. Comparison of potassium currents in rabbit atrial and ventricular cells. J Physiol. 1988 Nov;405:123–145. doi: 10.1113/jphysiol.1988.sp017325. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gwilt M., Arrowsmith J. E., Blackburn K. J., Burges R. A., Cross P. E., Dalrymple H. W., Higgins A. J. UK-68,798: a novel, potent and highly selective class III antiarrhythmic agent which blocks potassium channels in cardiac cells. J Pharmacol Exp Ther. 1991 Jan;256(1):318–324. [PubMed] [Google Scholar]
  12. Kiyosue T., Arita M. Late sodium current and its contribution to action potential configuration in guinea pig ventricular myocytes. Circ Res. 1989 Feb;64(2):389–397. doi: 10.1161/01.res.64.2.389. [DOI] [PubMed] [Google Scholar]
  13. Lederer W. J., Niggli E., Hadley R. W. Sodium-calcium exchange in excitable cells: fuzzy space. Science. 1990 Apr 20;248(4953):283–283. doi: 10.1126/science.2326638. [DOI] [PubMed] [Google Scholar]
  14. Lis R., Morgan T. K., Jr, DeVita R. J., Davey D. D., Lumma W. C., Jr, Wohl R. A., Diamond J., Wong S. S., Sullivan M. E. Synthesis and antiarrhythmic activity of novel 3-alkyl-1-[omega-[4-[(alkylsulfonyl)amino]phenyl]-omega- hydroxyalkyl]-1H-imidazolium salts and related compounds. J Med Chem. 1987 Apr;30(4):696–704. doi: 10.1021/jm00387a020. [DOI] [PubMed] [Google Scholar]
  15. Lumma W. C., Jr, Wohl R. A., Davey D. D., Argentieri T. M., DeVita R. J., Gomez R. P., Jain V. K., Marisca A. J., Morgan T. K., Jr, Reiser H. J. Rational design of 4-[(methylsulfonyl)amino]benzamides as class III antiarrhythmic agents. J Med Chem. 1987 May;30(5):755–758. doi: 10.1021/jm00388a001. [DOI] [PubMed] [Google Scholar]
  16. Lynch J. J., Wilber D. J., Montgomery D. G., Hsieh T. M., Patterson E., Lucchesi B. R. Antiarrhythmic and antifibrillatory actions of the levo- and dextrorotatory isomers of sotalol. J Cardiovasc Pharmacol. 1984 Nov-Dec;6(6):1132–1141. [PubMed] [Google Scholar]
  17. Matsuda H., Noma A. Isolation of calcium current and its sensitivity to monovalent cations in dialysed ventricular cells of guinea-pig. J Physiol. 1984 Dec;357:553–573. doi: 10.1113/jphysiol.1984.sp015517. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Matsuura H., Ehara T., Imoto Y. An analysis of the delayed outward current in single ventricular cells of the guinea-pig. Pflugers Arch. 1987 Dec;410(6):596–603. doi: 10.1007/BF00581319. [DOI] [PubMed] [Google Scholar]
  19. Mitchell M. R., Powell T., Terrar D. A., Twist V. W. Calcium-activated inward current and contraction in rat and guinea-pig ventricular myocytes. J Physiol. 1987 Oct;391:545–560. doi: 10.1113/jphysiol.1987.sp016755. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Mitchell M. R., Powell T., Terrar D. A., Twist V. W. The effects of ryanodine, EGTA and low-sodium on action potentials in rat and guinea-pig ventricular myocytes: evidence for two inward currents during the plateau. Br J Pharmacol. 1984 Mar;81(3):543–550. doi: 10.1111/j.1476-5381.1984.tb10107.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Nokin P., Clinet M., Swillens S., Delisée C., Meysmans L., Chatelain P. Allosteric modulation of [3H]nitrendipine binding to cardiac and cerebral cortex membranes by amiodarone. J Cardiovasc Pharmacol. 1986 Sep-Oct;8(5):1051–1057. doi: 10.1097/00005344-198609000-00025. [DOI] [PubMed] [Google Scholar]
  22. Oinuma H., Miyake K., Yamanaka M., Nomoto K., Katoh H., Sawada K., Shino M., Hamano S. 4'-[(4-Piperidyl)carbonyl]methanesulfonanilides as potent, selective, bioavailable class III antiarrhythmic agents. J Med Chem. 1990 Mar;33(3):903–905. doi: 10.1021/jm00165a003. [DOI] [PubMed] [Google Scholar]
  23. Powell T., Terrar D. A., Twist V. W. Electrical properties of individual cells isolated from adult rat ventricular myocardium. J Physiol. 1980 May;302:131–153. doi: 10.1113/jphysiol.1980.sp013234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Sanguinetti M. C., Jurkiewicz N. K. Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol. 1990 Jul;96(1):195–215. doi: 10.1085/jgp.96.1.195. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Sheldon R. S., Hill R. J., Cannon N. J., Duff H. J. Amiodarone: biochemical evidence for binding to a receptor for class I drugs associated with the rat cardiac sodium channel. Circ Res. 1989 Aug;65(2):477–482. doi: 10.1161/01.res.65.2.477. [DOI] [PubMed] [Google Scholar]
  26. Shibasaki T. Conductance and kinetics of delayed rectifier potassium channels in nodal cells of the rabbit heart. J Physiol. 1987 Jun;387:227–250. doi: 10.1113/jphysiol.1987.sp016571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Terrar D. A., White E. Mechanisms and significance of calcium entry at positive membrane potentials in guinea-pig ventricular muscle cells. Q J Exp Physiol. 1989 Mar;74(2):121–139. doi: 10.1113/expphysiol.1989.sp003250. [DOI] [PubMed] [Google Scholar]
  28. Thomas G., Chung M., Cohen C. J. A dihydropyridine (Bay k 8644) that enhances calcium currents in guinea pig and calf myocardial cells. A new type of positive inotropic agent. Circ Res. 1985 Jan;56(1):87–96. doi: 10.1161/01.res.56.1.87. [DOI] [PubMed] [Google Scholar]
  29. Tsien R. W., Giles W., Greengard P. Cyclic AMP mediates the effects of adrenaline on cardiac purkinje fibres. Nat New Biol. 1972 Dec 6;240(101):181–183. doi: 10.1038/newbio240181a0. [DOI] [PubMed] [Google Scholar]

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